The present invention relates to oral sustained release pharmaceutical preparations in the form of microparticles of core drug particles surrounded by a pH controlled diffusion membrane.
As is well known, the maximum time of effectiveness in many pharmaceutical preparations, particularly those containing a drug such as aspirin, acetaminophen, propranolol, and dextromethorphan, etc. is only a few hours because of biological modification and/or elimination of the medication in the body. Consequently repeated dosages must be taken at frequent intervals to obtain long term therapeutic levels of drug. Furthermore, these drugs usually dissolve readily in the digestive juices and the total dosage is immediately fed into the blood stream. After high initial peak concentrations, the level of drug in the blood stream constantly decreases because of the biological elimination, so there is little or no therapeutic effect at the end of the period between dosages. As a result, the therapeutic effect fluctuates between dosages corresponding to the peaks and valleys in the level of drug in the blood as commonly measured by trough to peak ratios.
One common approach in attempting to provide a more constant drug level is to microencapsulate aspirin, for example, with a capsule wall material which provides a slower dissolution rate than free aspirin. The early work in that regard is represented by U.S. Pat. Nos. 3,155,590; 3,341,416; 3,488,418, and 3,531,418. Those patents, among others, disclose dispersing particles of aspirin in hot cyclohexane solution containing ethyl cellulose and then introducing a phase-separation inducing agent, such as butyl rubber or polyethylene. Upon cooling, the aspirin particles become coated with ethyl cellulose. The coated particles are then admixed with tabletting excipients and formed into dosage-sized tablets. When ingested, the tablets disintegrate rapidly and the individual particles of encapsulated aspirin are dispersed in the stomach. The gastric juices slowly diffuse through the capsule walls, dissovle the aspirin, and the dissolved aspirin slowly diffuses or leaches out through the capsule walls into the body. Although the resultant blood level content is sustained to a measurable extent, the aspirin is diffused into the body rapidly enough so there is an initially high blood level content which decreases quite rapidly within a few hours. These dissolution properties yield undesirable blood aspirin concentration versus time curves.
Guy U.S. Pat. No. 4,025,613 discloses a multi-layered tablet. One layer comprises aspirin coated with cellulose acetate phthalate and the other layer is free aspirin. With multi-layered microencapsulated particles, as discussed above, the dissolution rate decreases rapidly and the blood aspirin concentration at 2-3 hours must greatly exceed the therapeutic level in order to maintain adequate aspirin concentrations at 8 hours. As a result, efforts have been made to adjust the rate of dissolution and thus, control the timing of sustained drug release. See for example, Peters U.S. Pat. No. 3,492,397 where the dissolution rate is said to be controlled by adjusting the wax/ethyl cellulose ratio of the applied spray coating. See also U.S. Pats. No. 4,205,060 and 3,488,418 where it is indicated that the rate of dissolution can be controlled by varying the thickness of the coating.
Another method for providing an encapsulated pharmaceutical composition is discussed in published European patent application No. 77,956, published May 4, 1983. EPO Publication No. 77,596 discloses the use of microcapsules containing a coated core material such as pharmaceutical compounds and foodstuffs. The coating is applied by dispersing the core material into a solution containing ethyl cellulose as the wall-forming material. A phase separation of the ethyl cellulose from the dispersion of core material is carried out by cooling the dispersion. During this cooling, an enteric polymer material is incorporated into the ethyl cellulose coating walls by adding the enteric polymer material with stirring while the ethyl cellulose is still in the "gel" state. The enteric polymer material thus added penetrates, and is dispersed into the coating walls. When the microcapsules are administered, the release of the active compound does not generally occur in the stomach. However, the enteric polymer material is easily dissolved in the intestinal tract, thereby making the microcapsules porous. The porosity of the microcapsules promotes the rapid release of the active compound in the intestinal tract.
A similar approach is found in Japanese Patent Publication No. 12614/81 published Mar. 23, 1981. Japanese Publication No. 12614/81 discloses an enteric protective coating composition which will not readily dissolve in acidic gastric juices, but rapidly (within minutes) dissolves at the pH found in the intestines. The enteric coating is an aqueous dispersion of, for example. hydroxy propyl methyl cellulose phthalate, a gelling agent such as diacetin, and hydroxy propyl methyl cellulose. See, also. Japanese Patent Publication No. 11687/81, published Mar. 16, 1981, which uses hydroxy propyl methyl cellulose phthalate as an enteric coating.
The systems described in the EPO Japanese Publications are essentially "delayed" release mechanisms. There is a delay of medicament release in the stomach, but once the coated medicament reaches the intestines, the release of medication is rapid. There is no sustained-release of medication in the intestines. Furthermore, these systems use a "mixed" wall material which result in processing difficulties.
Finally reference is made to applicants' copending, application Ser. No. 017,988, filed Feb. 24, 1987. the disclosure of which is hereby incorporated by reference. In the copending application there is disclosed a sustained-release pharmaceutical preparation comprising a dual walled coated drug having an inner wall microencapsular control coating, such as ethyl cellulose, and an outer wall enteric coating, such as ethyl cellulose, and an outer wall enteric coating, such as cellulose acetate phthalate. Such a dual-walled material will release less than 10% per hour of core drug while in the stomach but will slowly release the core drug in the intestines to provide adequate drug levels for 8 or more hours. While this represents an improved result, film forming polymers designed to have permeability controlled by pH will provide increased flexibility in designing drug release profiles and will make processing easier and more economical by eliminating the need for a dual wall structure.
Thus, there remains a need for a film forming polymer with a permeability controlled by pH which can be used to coat core drug particles and produce microparticles which provide a delayed and sustained-release of drug.